Neurobiology of MIF in development and disease

MIF 在发育和疾病中的神经生物学

• 批准号: 7143547
• 负责人: BRADLEY D PEARCE
• 金额: $ 20.66万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7143547
• 关键词: angiotensin II; brain morphology; corticosterone; cytokine; developmental neurobiology; dopamine; genetically modified animals; haloperidol; inflammation; interleukin 1; interleukin 6; laboratory mouse; macrophage; migration inhibition factor; neurochemistry; neurogenesis; neuroimmunomodulation; neurotransmitter metabolism; pregnancy circulation; protein structure function; psychopharmacologic agent; stressor; tissue /cell culture; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Macrophage migration inhibitory factor (MIF) is a unique molecule that functions as a cytokine and a hormone, and is induced by infections and psychological stress in animal models. Moreover, MIF is highly abundant in the brain and appears to have enzymatic activity that may participate in dopamine metabolism. MIF is encoded by a single gene on human chromosome 22q11.2, and its amino acid sequence has minimal homology with other identified biological response modifiers in mammals. There is little data concerning the function of MIF in the brain, and there is a lack of information as to whether MIF is involved in neurological or psychiatric disorders. MIF amplifies proinflammatory cytokine production by interfering with the immunosuppressive properties of endogenous glucocorticoids. This effect of MIF during neurodevelopment has not been well studied. A confluence of data from other laboratories supports the idea that proinflammatory cytokines may constitute a common pathway for prenatal or perinatal brain injury due to diverse insults in humans. Thus, in Aim 1 we will use transgenic mice to investigate the role of MIF in maternal/fetal inflammatory responses and neurodevelopmental outcomes. These studies may provide clues to schizophrenia, which has been linked to chromosome 22q11-12, and is associated with aberrant neurodevelopment due to prenatal or perinatal obstetric complications. We will also test the offspring of dams treated with inducers of MIF for changes in prepulse inhibition (PPI) and alterations in hippocampal volume as adults. Likewise, the idea that MIF is involved in dopaminergic neurotransmission warrants further study. This will be explored in Aim 2. We will tests the idea that mice lacking MIF (knockout mice) will have a reduced number of dopamine neurons and abnormal catecholamine metabolism. In addition, we will determine whether the dopamine antagonist, haloperidol, can influence blood levels of MIF. In AIM 2, we also plan to examine the relationship between MIF and the peptide, angiotensin II. Studies by other investigators have shown that this peptide can be made locally in the brain and is capable of inducing MIF. It has also been shown that angiotensin II promotes dopamine neurotransmission, and therefore we will determine whether this action is dependent on MIF. Besides schizophrenia, these studies could provide insight into Parkinson's disease, and maternal mental illnesses.

描述（由申请人提供）：巨噬细胞迁移抑制因子（MIF）是一种独特的分子，具有细胞因子和激素的功能，在动物模型中由感染和心理压力诱导。此外，MIF 在大脑中含量很高，并且似乎具有可能参与多巴胺代谢的酶活性。 MIF由人类染色体22q11.2上的单个基因编码，其氨基酸序列与哺乳动物中其他已识别的生物反应修饰剂具有极小的同源性。关于 MIF 在大脑中的功能的数据很少，并且缺乏关于 MIF 是否与神经或精神疾病有关的信息。 MIF 通过干扰内源性糖皮质激素的免疫抑制特性来放大促炎细胞因子的产生。 MIF 在神经发育过程中的这种作用尚未得到充分研究。来自其他实验室的数据汇集支持这样的观点，即促炎细胞因子可能构成由于人类多种损伤而导致产前或围产期脑损伤的常见途径。因此，在目标 1 中，我们将使用转基因小鼠来研究 MIF 在母体/胎儿炎症反应和神经发育结果中的作用。这些研究可能为精神分裂症提供线索，精神分裂症与染色体 22q11-12 有关，并与产前或围产期产科并发症导致的神经发育异常有关。我们还将测试用 MIF 诱导剂治疗的母鼠后代的前脉冲抑制 (PPI) 变化和成年后海马体积的变化。同样，MIF 参与多巴胺能神经传递的观点值得进一步研究。这将在目标 2 中进行探讨。我们将测试缺乏 MIF 的小鼠（基因敲除小鼠）的多巴胺神经元数量减少和儿茶酚胺代谢异常的想法。此外，我们将确定多巴胺拮抗剂氟哌啶醇是否可以影响 MIF 的血液水平。在 AIM 2 中，我们还计划检查 MIF 和肽血管紧张素 II 之间的关系。其他研究人员的研究表明，这种肽可以在大脑中局部生成，并且能够诱导 MIF。研究还表明，血管紧张素 II 可以促进多巴胺神经传递，因此我们将确定这种作用是否依赖于 MIF。除了精神分裂症之外，这些研究还可以深入了解帕金森病和孕产妇精神疾病。